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Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells
S W Lowe1, T Jacks, D E Housman
1Center for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139.
Abstract:
p53-deficient mouse embryonic fibroblasts were used to establish a direct mechanism of tumor suppression by p53 involving the destruction of oncogene-expressing cells by apoptosis. The absence of p53 enhanced cell growth, appeared sufficient for immortalization, and allowed a single oncogene [adenovirus early region 1A (E1A)] to transform cells to a tumorigenic state. p53 suppressed transformation of E1A-expressing cells by apoptosis. Apoptosis was associated with p53 stabilization and was triggered by environmental signals that normally suppress cell growth. Absence of even a single p53 allele significantly enhanced cell growth and survival. Although abrogation of apoptosis allowed transformation by E1A alone, escape from apoptosis susceptibility was not a prerequisite for tumor growth. Consequently, p53 mutation could enhance the survival of malignant cells expressing oncogenes activated early in tumor progression.
Insights
The tumor suppressor protein p53 directly eliminates oncogene-expressing cells via apoptosis. Loss of p53 promotes cell growth and immortalization, enabling oncogenes to drive tumor formation.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The p53 protein is a critical tumor suppressor.
- Oncogene activation is a key step in cancer development.
- Apoptosis, or programmed cell death, is a mechanism to eliminate damaged cells.
Purpose of the Study:
- To elucidate the direct mechanism of tumor suppression by p53.
- To investigate the role of p53 in preventing oncogene-induced transformation.
- To understand how p53 deficiency impacts cell growth and apoptosis.
Main Methods:
- Utilized p53-deficient mouse embryonic fibroblasts.
- Introduced the adenovirus E1A oncogene into cells.
- Assessed cell growth, immortalization, transformation, and apoptosis.
- Analyzed p53 stabilization and its association with apoptosis.
Main Results:
- p53 deficiency enhanced cell growth, immortalization, and oncogene-induced transformation.
- p53 suppressed transformation by inducing apoptosis in E1A-expressing cells.
- Apoptosis was linked to p53 stabilization and triggered by growth-suppressive signals.
- Loss of even one p53 allele increased cell survival.
Conclusions:
- p53 directly suppresses tumors by inducing apoptosis in oncogene-expressing cells.
- p53 deficiency facilitates oncogene-driven transformation and tumor progression.
- p53 mutation can enhance the survival of malignant cells with activated oncogenes.